Microfluidic devices for cell culture typically need to be perfused with fluid media at an extremely low flow rate, such as between 30 μL/hr and 5 mL/hr. Moreover, in some experiments, the media must be flowed at known rates for several weeks. Additionally, many experiments need tens of channels to be able to explore a number of test conditions, in order to gain statistically significant results. Therefore, the devices are preferably tested simultaneously using the same setup. What is more, the footprint of the perfusion system must be small enough to allow for the integration of many devices (e.g., at least 12 devices) in a reasonable space.
Some existing technologies attempt to solve fluid-flow issues using rollers on a stepper motor to engage an elastic polymer with channels in it. As the motor spins, it pushes the fluid through the cartridge and the chips. This pumping scheme, however, cannot be sufficiently minimized. Additionally, because the pumping mechanism must be engaged with the cartridge, the pump-head must reside inside an incubated space. Finally, the microfluidic peristaltic pumping system relies on a material that must be resistant to frictional/shearing forces, have a low elastic modulus, be injection moldable or otherwise mass producible, be bondable (to allow creating microfluidic channels), be non-cytotoxic, and not absorb or substantially adsorb small molecules. To date, it appears that there is no such material that sufficiently meets all of these demands.
Other alternative pumping technologies are traditional peristaltic pumps and syringe pumps. Traditional peristaltic pumps tend to be bulky, and they require specialized tubing to be strung up through the pump before each use. In turn, the tubing needed to attain the low flow-rates typical of organs-on-chips is difficult to connectorize and assemble with chips or cartridges. Syringe pumps are also bulky, and they provide no simple way to change out syringes after the entire syringe volume has been discharged.
Further, accumulation of gas bubbles poses risks to microfluidic systems and components thereof. Gas bubbles can have many detrimental effects when introduced into or formed inside of microfluidic channels. For example, large capillary forces that are characteristic of bubble interfaces confined to small dimensions can cause difficulty in removing bubbles from the microfluidic channels. In microfluidic devices that include cells, gas bubbles can be especially detrimental for several additional reasons. For example, stagnant bubbles sitting on top of the cells can starve them of critical nutrients. Further, even when only passing by cells, bubbles can damage the cells due to high shear and capillary forces (e.g., by delaminating the cell layer). Many methods have been proposed for preventing bubbles from entering microfluidic devices or being formed within the devices. However, it is very difficult to completely prevent bubble-generation events or bubble-accumulation events within a microfluidic system. Thus, it is unlikely that bubbles will be fully eliminated over the duration of a long-term experiment.
Aspects of the present invention provide new fluid-pumping systems and methods for microfluidic devices that provide a consistent and reliable flow of media to the microchannels and/or provide systems and methods for preventing, inhibiting, or limiting damage caused by bubbles that are generated or accumulated.